Academic Staff

Dr Hayley S Mountford

Postdoctoral Researcher

Department of Biological and Medical Sciences

Faculty of Health and Life Sciences

Phone number:
+ 44 (0)1865 483276

Email:
hmountford@brookes.ac.uk

Location:
Headington Campus, Oxford

I am an early career researcher in the Newbury lab. I use a range of bioinformatic and molecular biology techniques to study how genetics influences human learning through extreme traits. My main interests are:

how genetic variants underpin common neurodevelopmental conditions such as developmental language delay

Speech and language disorders are a common childhood developmental issue (7% of children) (Norbury et al. 2016) and result in an increased lifetime risk of mental health issues and poor life outcomes (Conti-Ramsden et al. 2008). Despite being so common, we understand little of the biology underpinning disorders of speech, however, it is becoming increasingly apparent that genetic risk, or susceptibility, plays an important role. The identification of genetic risk factors for speech and language disorder may also help explain why language ability is so often affected in related disorders such as autism spectrum disorder, developmental dyslexia, intellectual learning disability or ADHD.

Using recent advances in genetic technologies, I am investigating genetic contributions to speech and language disorders in the inhabitants of Robinson Crusoe Island (RCI), Chile. The island was colonised in the late 19th century, and is physically isolated, over 600km away, from the mainland. Most of the people who live there today are related to the original 62 founders. Two-thirds of Islander children have speech and language disorder, 10-fold higher than expected.

The Genetics of Face Recognition

We know there is something special about the way we interact with faces. From an early age, both animals and humans show a clear preference for faces over other visual stimuli - new born babies will actively choose to look at images of faces (Goren et al 1975), and can identify their mother over other females after only two days (Bushnell 1989). The ability to discriminate between faces allows us to establish individual identity and plays an important role in human bonding and social exchange. The lack of ability to recognise peers by their faces often leads to struggles with social isolation and mental health issues. It is a fundamental and vital part of human behaviour, one which develops so early in our development, that we almost take it for granted. Despite it being pivotal to our success as a social species, we understand little of how the brain recognises faces, or which neuro-molecular pathways are involved in this essential process.

Super recognisers can recognise faces they have only glimpsed before. Most people can recognise about 20% of the faces they see, whereas a super recogniser can remember up to 95%. This super ability is thought to occur in less than 1% of the population.

Face recognition plays an important role in the Metropolitan Police who use super recognisers to identify suspects from CCTV footage. Following the 2011 London riots, a single super recogniser identified 190 suspects from grainy images and footage, in stark comparison with the Met’s state-of-the-art computer software that only successfully identified one.

https://www.youtube.com/watch?v=PuPfQ8UZTGQ

In collaboration with Dr Josh Davis (University of Greenwich), we are studying the genetics of individuals with extreme face recognition ability - super recognisers.

If you think you might be a super recogniser, click here to take the test http://superrecognisers.com/

Robinson Crusoe Island is a geographically and socially isolated settlement located over 600km west of the Port of Valparíso, Chile. An unusually high incidence (30%) of the Chilean equivalent of developmental language disorder (TEL) has been reported in Islander children, with 90% of these affected children found to be direct descendants of a pair of original founder-brothers, therefore strongly suggesting a shared genetic basis.

Here we utilise whole-genome sequencing to investigate potential underlying variants in a panel of thirty-four genes known to play a role in language disorders, in seven TEL affected and ten unaffected islanders. We use this targeted approach to look for rare, shared variants that may underlie the diagnosis of TEL in a Mendelian genetic model. We go on to test whether the overall burden of rare variants is enriched in individuals affected by TEL or with Islanders related to the founder-brother lineage.

In the absence of explanatory rare variants, we further investigate these candidate genes within a complex model of inheritance, where inheriting a small number of moderate impact common variants may increase susceptibility of developing TEL. We examine if any variants segregate with affection status or with founder-brother-related status, and therefore may increase risk of developing a language disorder. Finally, we perform a pooled, gene-based tests to evaluate relationships between combined variation across candidate genes and TEL affection status.

Mountford HS, Newbury DF, 'The Genomic Landscape of Language Disorders: Insights into Evolution'Journal of Language Evolution 3 (1) (2018) pp.49-58ISSN: 2058-4571 eISSN: 2058-458X Abstract Studies of severe, monogenic forms of language disorders have revealed important insights into the mechanisms that underpin language development and evolution. It is clear that monogenic mutations in genes such as FOXP2 and CNTNAP2 only account for a small proportion of language disorders seen in children, and the genetic basis of language in modern humans is highly complex and poorly understood. In this review, we examine why we understand so little of the genetic landscape of language disorders, and how the genetic background of an individual greatly affects the way in which a genetic change is expressed. We discuss how the underlying genetics of language disorders has informed our understanding of language evolution, and how recent advances may obtain a clearer picture of language capacity in ancient hominins. Website

Stroud D, Maher M, Lindau C, Vogtle FN, Frazier A, Surgenor E, Mountford HS, Singh A, Bonas M, Oeljeklaus S, Warscheid B, Meisinger C, Thorburn D, Ryan M, 'COA6 is a mitochondrial complex IV assembly factor critical for biogenesis of mtDNA-encoded COX2'Human Molecular Genetics 24 (19) (2015) pp.5404-5415ISSN: 0964-6906 eISSN: 1460-2083 Abstract Biogenesis of complex IV of the mitochondrial respiratory chain requires assembly factors for subunit maturation, co-factor attachment and stabilization of intermediate assemblies. A pathogenic mutation in COA6, leading to substitution of a conserved tryptophan for a cysteine residue, results in a loss of complex IV activity and cardiomyopathy. Here, we demonstrate that the complex IV defect correlates with a severe loss in complex IV assembly in patient heart but not fibroblasts. Complete loss of COA6 activity using gene editing in HEK293T cells resulted in a profound growth defect due to complex IV deficiency, caused by impaired biogenesis of the copper-bound mitochondrial DNA-encoded subunit COX2 and subsequent accumulation of complex IV assembly intermediates. We show that the pathogenic mutation in COA6 does not affect its import into mitochondria but impairs its maturation and stability. Furthermore, we show that COA6 has the capacity to bind copper and can associate with newly translated COX2 and the mitochondrial copper chaperone SCO1. Our data reveal that COA6 is intricately involved in the copper-dependent biogenesis of COX2.Website

Mordaunt DA, Jolley A, Balasubramaniam S, Thorburn DR, Mountford HS, Compton AG, Nicholl J, Manton N, Clark D, Bratkovic D, Friend K, Yu S, 'Phenotypic variation of TTC19-deficient mitochondrial complex III deficiency: A case report and literature review'American Journal of Medical Genetics Part A 167 (6) (2015) pp.1330-1336ISSN: 1552-4825 Abstract Isolated mitochondrial respiratory chain complex III deficiency has been described in a heterogeneous group of clinical presentations in children and adults. It has been associated with mutations in MT-CYB, the only mitochondrial DNA encoded subunit, as well as in nine nuclear genes described thus far: BCS1L, TTC19, UQCRB, UQCRQ, UQCRC2, CYC1, UQCC2, LYRM7, and UQCC3. BCS1L, TTC19, UQCC2, LYRM7, and UQCC3 are complex III assembly factors. We report on an 8-year-old girl born to consanguineous Iraqi parents presenting with slowly progressive encephalomyopathy, severe failure to thrive, significant delays in verbal and communicative skills and bilateral retinal cherry red spots on fundoscopy. SNP array identified multiple regions of homozygosity involving 7.5% of the genome. Mutations in the TTC19 gene are known to cause complex III deficiency and TTC19 was located within the regions of homozygosity. Sequencing of TTC19 revealed a homozygous nonsense mutation at exon 6 (c.937C > T; p.Q313X). We reviewed the phenotypes and genotypes of all 11 patients with TTC19 mutations leading to complex III deficiency (including our case). The consistent features noted are progressive neurodegeneration with Leigh-like brain MRI abnormalities. Significant variability was observed however with the age of symptom onset and rate of disease progression. The bilateral retinal cherry red spots and failure to thrive observed in our patient are unique features, which have not been described, in previously reported patients with TTC19 mutations. Interestingly, all reported TTC19 mutations are nonsense mutations. The severity of clinical manifestations however does not specifically correlate with the residual complex III enzyme activities.Website

Mutations in genes encoding components of the Brahma-associated factor (BAF) chromatin remodeling complex have recently been shown to contribute to multiple syndromes characterised by developmental delay and intellectual disability. ARID1B mutations have been identified as the predominant cause of Coffin-Siris syndrome and have also been shown to be a frequent cause of nonsyndromic intellectual disability. Here, we investigate the molecular basis of a patient with an overlapping but distinctive phenotype of intellectual disability, plantar fat pads and facial dysmorphism.

Methods/results

High density microarray analysis of the patient demonstrated a heterozygous deletion at 6q25.3, which resulted in the loss of four genes including AT Rich Interactive Domain 1B (ARID1B). Subsequent quantitative real-time PCR analysis revealed ARID1B haploinsufficiency in the patient. Analysis of both patient-derived and ARID1B knockdown fibroblasts after serum starvation demonstrated delayed cell cycle re-entry associated with reduced cell number in the S1 phase. Based on the patient’s distinctive phenotype, we ascertained four additional patients and identified heterozygous de novo ARID1B frameshift or nonsense mutations in all of them.

Conclusions

This study broadens the spectrum of ARID1B associated phenotypes by describing a distinctive phenotype including plantar fat pads but lacking the hypertrichosis or fifth nail hypoplasia associated with Coffin-Siris syndrome. We present the first direct evidence in patient-derived cells that alterations in cell cycle contribute to the underlying pathogenesis of syndromes associated with ARID1B haploinsufficiency.

Tucker EJ, Wanschers BFJ, Szklarczyk R, Mountford HS, Wijeyeratne XW, van den Brand MAM, Leenders AM, Rodenburg RJ, Reljić B, Compton AG, Frazier AE, Bruno DL, Christodoulou J, Endo H, Ryan MT, Nijtmans LG, Huynen MA, Thorburn DR, 'Mutations in the UQCC1-Interacting Protein, UQCC2, cause human Complex III deficiency associated with perturbed cytochrome b protein expression'PLoS Genetics 9 (12) (2013)ISSN: 1553-7390 Abstract Mitochondrial oxidative phosphorylation (OXPHOS) is responsible for generating the majority of cellular ATP. Complex III (ubiquinol-cytochrome c oxidoreductase) is the third of five OXPHOS complexes. Complex III assembly relies on the coordinated expression of the mitochondrial and nuclear genomes, with 10 subunits encoded by nuclear DNA and one by mitochondrial DNA (mtDNA). Complex III deficiency is a debilitating and often fatal disorder that can arise from mutations in complex III subunit genes or one of three known complex III assembly factors. The molecular cause for complex III deficiency in about half of cases, however, is unknown and there are likely many complex III assembly factors yet to be identified. Here, we used Massively Parallel Sequencing to identify a homozygous splicing mutation in the gene encoding Ubiquinol-Cytochrome c Reductase Complex Assembly Factor 2 (UQCC2) in a consanguineous Lebanese patient displaying complex III deficiency, severe intrauterine growth retardation, neonatal lactic acidosis and renal tubular dysfunction. We prove causality of the mutation via lentiviral correction studies in patient fibroblasts. Sequence-profile based orthology prediction shows UQCC2 is an ortholog of the Saccharomyces cerevisiae complex III assembly factor, Cbp6p, although its sequence has diverged substantially. Co-purification studies show that UQCC2 interacts with UQCC1, the predicted ortholog of the Cbp6p binding partner, Cbp3p. Fibroblasts from the patient with UQCC2 mutations have deficiency of UQCC1, while UQCC1-depleted cells have reduced levels of UQCC2 and complex III. We show that UQCC1 binds the newly synthesized mtDNA-encoded cytochrome b subunit of complex III and that UQCC2 patient fibroblasts have specific defects in the synthesis or stability of cytochrome b. This work reveals a new cause for complex III deficiency that can assist future patient diagnosis, and provides insight into human complex III assembly by establishing that UQCC1 and UQCC2 are complex III assembly factors participating in cytochrome b biogenesis.Website

Mill P, Lockhart PJ, Fitzpatrick E, Mountford HS, Hall EA, Reijns MAM, Keighren M, Bahlo M, Bromhead CJ, Budd P, Aftimos S, Delatycki MB, Savarirayan R, Jackson IJ, Amor DJ, 'Human and mouse mutations in WDR35 cause short-rib polydactyly syndromes due to abnormal ciliogenesis'American Journal of Human Genetics 88 (4) (2011) pp.508-515ISSN: 0002-9297 Abstract Defects in cilia formation and function result in a range of human skeletal and visceral abnormalities. Mutations in several genes have been identified to cause a proportion of these disorders, some of which display genetic (locus) heterogeneity. Mouse models are valuable for dissecting the function of these genes, as well as for more detailed analysis of the underlying developmental defects. The short-rib polydactyly (SRP) group of disorders are among the most severe human phenotypes caused by cilia dysfunction. We mapped the disease locus from two siblings affected by a severe form of SRP to 2p24, where we identified an in-frame homozygous deletion of exon 5 in WDR35. We subsequently found compound heterozygous missense and nonsense mutations in WDR35 in an independent second case with a similar, severe SRP phenotype. In a mouse mutation screen for developmental phenotypes, we identified a mutation in Wdr35 as the cause of midgestation lethality, with abnormalities characteristic of defects in the Hedgehog signaling pathway. We show that endogenous WDR35 localizes to cilia and centrosomes throughout the developing embryo and that human and mouse fibroblasts lacking the protein fail to produce cilia. Through structural modeling, we show that WDR35 has strong homology to the COPI coatamers involved in vesicular trafficking and that human SRP mutations affect key structural elements in WDR35. Our report expands, and sheds new light on, the pathogenesis of the SRP spectrum of ciliopathies.Website

Stark Z, Bruno DL, Mountford HS, Lockhart PJ, Amor DJ, 'De novo 325 kb microdeletion in chromosome band 10q25.3 including ATRNL1 in a boy with cognitive impairment, autism and dysmorphic features.'European Journal of Medical Genetics 53 (5) (2010) pp.337-339ISSN: 1769-7212 Abstract We provide the first description of a patient with a heterozygous deletion of the Attractin-like (ATRNL1) gene. The patient presented with a novel and distinctive phenotype comprising dysmorphic facial appearance, ventricular septal defect, toe syndactyly, radioulnar synostosis, postnatal growth retardation, cognitive impairment with autistic features, and ataxia. A 325 kb de novo deletion in ATRNL1 was demonstrated using SNP microarray and confirmed by FISH analysis using BAC probes. Sequence analysis of the undeleted allele did not identify any alterations, suggesting that the phenotype was the result of haploinusfficiency. ATRNL1 and its paralog ATRN are highly conserved transmembrane proteins thought to be involved in cell adhesion and signalling events. The phenotype of mice with homozygous Atrn mutations overlaps considerably with the features observed in our patient. We therefore postulate that our patient’s phenotype is caused by the deletion of ATRNL1, and provide further insight into the role of ATRNL1 in human development.Website

Kaur S, Cogan NOI, Ye G, Baillie RC, Hand ML, Ling AE, McGearey AK, Kaur J, Hopkins CJ, Todorovic M, Mountford HS, Edwards D, Batley J, Burton W, Salisbury P, Gororo N, Marcroft S, Kearney G, Smith KF, Forster JW, Spangenberg G, 'Genetic map construction and QTL mapping of resistance to blackleg (Leptosphaeria maculans) disease in Australian canola (Brassica napus L.) cultivars.'TAG Theoretical and Applied Genetics 120 (1) (2009) pp.71-83ISSN: 0040-5752 Abstract Genetic map construction and identification of quantitative trait loci (QTLs) for blackleg resistance were performed for four mapping populations derived from five different canola source cultivars. Three of the populations were generated from crosses between single genotypes from the blackleg-resistant cultivars Caiman, Camberra and AVSapphire and the blackleg-susceptible cultivar Westar10. The fourth population was derived from a cross between genotypes from two blackleg resistant varieties (Rainbow and AVSapphire). Different types of DNA-based markers were designed and characterised from a collection of 20,000 EST sequences generated from multiple Brassica species, including a new set of 445 EST-SSR markers of high value to the international community. Multiple molecular genetic marker systems were used to construct linkage maps with locus numbers varying between 219 and 468, and coverage ranging from 1173 to 1800 cM. The proportion of polymorphic markers assigned to map locations varied from 70 to 89% across the four populations. Publicly available simple sequence repeat markers were used to assign linkage groups to reference nomenclature, and a sub-set of mapped markers were also screened on the Tapidor × Ningyou (T × N) reference population to assist this process. QTL analysis was performed based on percentage survival at low and high disease pressure sites. Multiple QTLs were identified across the four mapping populations, accounting for 13–33% of phenotypic variance (Vp). QTL-linked marker data are suitable for implementation in breeding for disease resistance in Australian canola cultivars. However, the likelihood of shifts in pathogen race structure across different geographical locations may have implications for the long-term durability of such associations.Website

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